Targeted inhibition of NEK7 preventing sepsis-induced cardiomyopathy by inhibiting NLRP3 inflammasome

Abstract

Background: Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis; however, its pathogenesis remains elusive. This study aims to investigate the role of NMA-related kinase 7 (NEK7) in SIC.

Methods: C57BL/6 mice were stimulated with lipopolysaccharide (LPS) to assess NEK7 expression in the myocardium. AAV-shNEK7 was administered to improve cardiac function and survival rates. HL-1 cardiomyocytes were treated with si-NEK7 after LPS stimulation, and cell viability was measured. Molecular docking analysis and co-immunoprecipitation assays were used to validate the interaction between NEK7 and the NLRP3 inflammasome.

Results: NEK7 was significantly upregulated in the myocardium of LPS-stimulated C57BL/6 mice. Administration of AAV-shNEK7 improved cardiac function and enhanced survival rates. In LPS-stimulated HL-1 cardiomyocytes, si-NEK7 treatment increased cell viability compared to control cells, due to the suppression of pyroptosis through attenuation of NLRP3 inflammasome activation. Molecular docking analysis and co-immunoprecipitation assays confirmed that targeting NEK7 inhibits its interaction with NLRP3, thereby suppressing inflammasome activation and providing a protective effect.

Conclusions: NEK7 plays a crucial role in SIC by facilitating NLRP3 inflammasome activation. Targeting NEK7 presents a potential therapeutic approach for SIC.

Keywords: NLRP3 inflammasome; NMA-related kinase 7; Pyroptosis; Sepsis-induced cardiomyopathy.